The aldol reaction is one of the fundamental synthetic routes used by organic chemists to form new carbon-carbon bonds. The reaction involves the addition of a first aldehyde or ketone, as a nucleophile, to a second aldehyde or ketone that acts as an electrophile. Mechanistically, the α-carbon atom of the first aldehyde or ketone adds to the carbonyl carbon of the second aldehyde or ketone. The product is a β-hydroxy aldehyde (i.e., an “aldol”) or ketone, which may serve as an intermediate in the context of a more complex reaction, or may represent the final product. Conventionally, aldol reactions involve a preliminary step in which the first aldehyde or ketone is converted to a nucleophile by forming the corresponding enolate, using a base, or the corresponding enol, using an acid.
Over the last three decades, seminal research has established the aldol reaction as the principal chemical reaction for the stereoselective construction of complex polyol architecture. Evans et al. (1979) J. Am. Chem. Soc. 101:6120; Evans et al. (1981) J. Am. Chem. Soc. 103:2127; Heathcock, C. H. Asymmetric Synthesis; Morrion, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, part B, p 111; Danda et al. (1980) J. Org. Chem. 55:173; Masamune et al. (1981) J. Am. Chem. Soc. 103:1566; Masamune et al. (1986) J. Am. Chem. Soc. 108:8279; Mukaiyama, “The Directed Aldol Reaction,” in Organic Reactions, New York, 1982; Vol. 28, p 203; Kobayashi et al. (1993) Tetrahedron 49:1761. More recently, several researchers have described attempts to achieve enantioselective “direct” aldol reactions, i.e., aldol reactions that do not require the pregeneration of enolates or enolate equivalents. See, e.g., List et al. (2000) J. Am. Chem. Soc. 122:2395; Notz et al. (2000) J. Am. Chem. Soc. 122:7386; Trost et al. (2000) J. Am. Chem. Soc. 122:12003; Yamada et al. (1997) Angew. Chem. Int. Ed. Engl. 36:1871; Yoshikawa et al. (1999) J. Am. Chem. Soc. 121:4168. These efforts have given rise to a new goal, the development of catalytic methods that allow the direct coupling of aldehyde substrates, illustrated in Scheme 1: 
To date, direct, enantioselective coupling of aldehyde substrates has been achieved only with enzymatic catalysis (see Gijsen et al. (1994) J. Am. Chem. Soc. 116:8422). In addition, the enantioselective aldol coupling of non-equivalent aldehydes has been viewed as a particularly formidable synthetic challenge, because of (i) the propensity of aldehydes to polymerize under metal-catalyzed conditions and (ii) the mechanistic requirement that non-equivalent aldehydes must selectively partition into two discrete components, a nucleophilic donor and an electrophilic acceptor. Accordingly, an efficient and operationally simple method for carrying out direct, enantioselective coupling of aldehydes, including non-equivalent aldehydes, would be an enormously powerful tool in the field of synthetic organic chemistry. The present invention now provides such a method using chiral organic catalysts.
Many catalysts of organic reactions, including aldol coupling reactions, are organometallic complexes. Unfortunately, many organometallic reagents are expensive, and, depending on their catalytic activity, they may not be commercially viable. Moreover, many organometallic complexes are useful in conjunction with very specific reactants and reactions, a problem that is exacerbated in the catalysis of reactions leading to chiral molecules, particularly the conversion of either chiral or achiral molecules via enantioselective catalysis to provide a chiral product. Despite the observed need, relatively few asymmetric transformations have been reported that employ organic molecules as reaction catalysts. Recently, as described in U.S. Pat. No. 6,307,057 to MacMillan and U.S. Pat. No. 6,369,243 to MacMillan et al., certain organic catalysts have been synthesized that facilitate enantioselective transformations by lowering the LUMO (lowest unoccupied molecular orbital) of a reactant such as an α,β-unsaturated carbonyl compound to facilitate reaction thereof. The organic catalysts are acid addition salts of nonmetallic compounds containing a Group 15 or Group 16 heteroatom, e.g., salts of chiral amines, exemplified by the imidazolidinone salt (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-one hydrochloride. 
It has now been quite unexpectedly discovered that certain imidazolidinones and other chiral organic compounds, including, without limitation, those described in the '057 and '243 patents, are useful in catalyzing aldol coupling reactions of aldehydes in an enantioselective fashion. The invention represents a significant advance in the field of synthetic organic chemistry, insofar as the present methodology enables not only enantioselective aldol reactions of aldehydes, but also direct, enantioselective aldol coupling reactions using aldehydes as both aldol donor and aldol acceptor. The method provides for the enantioselective access to β-hydroxy aldehydes—important synthons in polypropionate and polyacetate natural product synthesis—as well as hydroxyvinyl polymers and oxygen heterocycles, including naturally occurring and synthetic sugars.